One of the most frequently used controlled release systems consists of a biologically active agent physically incorporated in a polymeric matrix, shaped to a convenient form and implanted by injection. The rate of release of the active agent is then controlled by diffusion through the polymeric matrix, and is only weakly dependent on the external conditions. According to Fick's first law, the diffusion rate is proportional to the concentration gradient across the membrane and to the diffusion coefficient of the permeant in the matrix.
In the last decades the interest in using biodegradable polymers as matrix drug delivery has grown significantly for two essential reasons. First, the decline in release rate due to the depletion of the matrix can be compensated by the release of drug due to erosion of the polymer matrix. Second, the bioerosion of the polymer matrix avoids the difficult removal of the matrix by surgery. It is, however, important to note that a constant release is not always desirable. In many cases (for example, trypanocidal drugs) a high initial dose, followed by a constant or slowly declining drug release may produce the most desired therapeutic effect.
J. Heller, U.S. Pat. No. 4,639,366, describes a controlled release device comprising (a) a polymer with at least one labile backbone bond per repeat unit and at least one pendant acid functionality per thousand repeat units, and (b) a therapeutic or biologically active agent incorporated within or surrounded by the matrix of the polymer. These polymers may be prepared by reacting a polyol, preferably a diol, having a pendant acidic group with a polymer containing a labile backbone bond. Polymers mentioned for use in this reaction are polyorthoesters (including polyorthocarbonates), polyacetals, polyketals, polyesters and polyphosphazenes.
In U.S. Pat. No. 3,893,980 and in Macromolecules, 1977, Vol. 10, No. 4, pages 824-830, H. R. Allcock et al describe the synthesis of phosphazene high polymers with glycino ethyl ester, alanino methyl ester, leucino methyl ester, and phenylalanino methyl ester substituents by the interaction of poly(dichlorophosphazene) with amino acid esters. Total halogen replacement was achieved only with glycine ethyl ester. Replacement of the remaining chlorine could be effected by the subsequent introduction of methylamino groups as cosubstituents. The objective of this work was to determine whether the polymers could be biocompatible as solids or biodegradable to harmless hydrolysis products. If the products proved to be soluble in aqueous media, they could possibly be used as plasma extenders or carrier molecules for chemotherapeutic drugs. As pointed out in the patent, the methylamino groups were utilized in order to impart hydrophilicity to the polymers, a feature which was deemed by the patentees to be very important.
In Journal of Controlled Release, 1986, Vol. 3, pages 143-154, C. W. J. Grolleman et al describe the synthesis of bioerodible phosphazene polymers containing a model drug (phenylacetic acid) or a drug (naproxen) covalently bound to the chain through a spacer, L-lysine. Residual chlorine on the partially substituted polyphosphazene was replaced by reaction with glycine ethyl ester. Subsequent papers by Grolleman et al (Ibid., 1986, Vol. 4 pages 119-131; and pages 133-142) describe experiments in vitro and in vivo using such naproxen-substituted polyphosphazene drug release systems.